Patients with squamous cell carcinoma of the oral cavity are afflicted with a malignancy that frequently presents with advanced disease, and whose management often has profound effects upon these individual's speech, swallowing, cosmetic appearance, as well as survival. Unfortunately, despite advances in contemporary surgery and radiation therapy over the past thirty years, survival among these patients has remained essentially unaltered. Additionally, chemotherapy has shown little promise in the management of these cancers. Therefore, developing novel mechanisms of cessating these oral cancers may provide for important insights into the management of these patients. Initial investigations of wild-type p53 adenovirus has shown promise as a molecular intervention due to its function as a tumor suppressor gene and proposed role in apoptosis. However, significant advances are required in understanding the optimization of transduction efficiency in molecular therapy as well s increasing our understanding of the interaction of molecular intervention strategies in order to produce the desired effect of tumor cell demise. The applicant has elected to employ the adenovirus vector as a mechanism for molecular intervention due to its characteristic transient expression, efficacy of expression and ability to expand to high titers. Additionally, lack of permanent integration is favorable from a biosafety standpoint as compared to retrovirus vectors. This proposal, therefore, submits to further develop our understanding of molecular therapy for oral cavity squamous carcinomas through the following specific aim: 1. To determine the maximal transfection efficiency of adenovirus vectors in the transient expression of marker genes in oral squamous carcinomas. 2. To develop in vivo strategies for effective adenoviral vector transduction of oral squamous carcinomas. 3. To determine the effectiveness of transient expression of wild-type p53, p16, p21 (CIP/WAF1), and pRB105 independently and in combination in the growth inhibition and induction of apoptosis in oral squamous carcinomas. 4. To determine whether regulation of transcription factors E2F-1 and DP-1, and the induced gene, p21 (CIP/WAF1), which are downstream of p53, can potentiate the growth inhibition and induction of apoptosis in oral squamous carcinoma cells.